WO2015137846A1 - Composés amides et procédés de leur production et utilisation - Google Patents

Composés amides et procédés de leur production et utilisation Download PDF

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Publication number
WO2015137846A1
WO2015137846A1 PCT/RU2015/000121 RU2015000121W WO2015137846A1 WO 2015137846 A1 WO2015137846 A1 WO 2015137846A1 RU 2015000121 W RU2015000121 W RU 2015000121W WO 2015137846 A1 WO2015137846 A1 WO 2015137846A1
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substitute sheet
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alkyl
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PCT/RU2015/000121
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English (en)
Russian (ru)
Inventor
Владимир Евгеньевич НЕБОЛЬСИН
Татьяна Александровна КРОМОВА
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Общество С Ограниченной Ответственностью "Фарминтерпрайсез"
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Priority to ES15761359T priority Critical patent/ES2938085T3/es
Priority to JP2016575291A priority patent/JP2017511374A/ja
Priority to FIEP15761359.7T priority patent/FI3118211T3/fi
Priority to EP18191137.1A priority patent/EP3431469A1/fr
Priority to CA2941900A priority patent/CA2941900C/fr
Priority to US15/125,460 priority patent/US20170183318A1/en
Priority to MX2016011771A priority patent/MX2016011771A/es
Application filed by Общество С Ограниченной Ответственностью "Фарминтерпрайсез" filed Critical Общество С Ограниченной Ответственностью "Фарминтерпрайсез"
Priority to SG11201607535VA priority patent/SG11201607535VA/en
Priority to EA201691694A priority patent/EA035545B1/ru
Priority to CN201580023692.4A priority patent/CN106459144A/zh
Priority to KR1020167027752A priority patent/KR102410255B1/ko
Priority to EP15761359.7A priority patent/EP3118211B1/fr
Priority to KR1020187021614A priority patent/KR20180088510A/ko
Priority to AU2015230061A priority patent/AU2015230061B2/en
Priority to IL247704A priority patent/IL247704B/en
Priority to UAA201610353A priority patent/UA121468C2/uk
Publication of WO2015137846A1 publication Critical patent/WO2015137846A1/fr
Priority to AU2018205206A priority patent/AU2018205206A1/en
Priority to US15/998,847 priority patent/US20180362481A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/05—Dipeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C07D209/16—Tryptamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/24—Radicals substituted by nitrogen atoms not forming part of a nitro radical
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
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    • C07D237/08—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
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    • C07D261/08—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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Definitions

  • the present invention relates to medicine, in particular, to the use of compounds of the general formula I or their pharmaceutically acceptable salts for the prevention and treatment of diseases caused by RNA and / or DNA-containing viruses and related diseases.
  • Viral infections are a huge public health problem. Antiviral drugs for most dangerous and especially dangerous viral infections have not been developed, and existing ones are often toxic to humans or have insufficient effectiveness. Most existing or under development drugs act through specific interactions with certain viral proteins. Such drugs have a limited spectrum of action and contribute to the rapid emergence of resistant variants of viruses.
  • class I includes viruses whose genome is double-stranded DNA
  • classes IV and V include viruses containing single-stranded (+) or (-) RNA.
  • Adenovirus family including the genus Mastadenovirus, for which 7 groups A to G are known.
  • adenoviruses cause a number of diseases, including conjunctivitis, gastroenteritis, hepatitis, myocarditis and pneumonia. Children under 5 years of age are most susceptible to adenovirus infection. In the world from 5 to 7% of all respiratory infections in children are caused by adenoviruses. Some serotypes (e.g. 14) cause severe, potentially fatal pneumonia. Subgroup A viruses cause gastric tract diseases, while subgroup B and C viruses are associated with respiratory tract infection. Viruses of subgroups B (type 3), D and E cause conjunctivitis. Subgroup E viruses are also associated with respiratory tract infection. Subgroup F and G viruses cause gastroenteritis.
  • SUBSTITUTE SHEET (RULE 26) Another class I family is the herpesvirus family, which includes the genus simplexvirus, to which the herpes simplex viruses of the 1st and 2nd type (AHP-1 and AHP-2) belong. After the initial infection, these viruses cause a latent infection, which persists throughout life with periodic activation. Infection in children can be either asymptomatic or severe with involvement of the central nervous system. Especially dangerous is the infection of HSV in newborns before delivery or at the time of delivery, which can cause diseases of the eyes, skin, central nervous system or even lead to disseminated infection.
  • AHP-2 causes a genital infection, mainly sexually transmitted. It is estimated that in 2012 in the world 417 million people aged 15-49 years are infected with the hepatitis B virus-2, which is 11.3%. 267 million of this number are women. At the same time, 19.2 million of the total number of infected were infected in 2012, which is 0.5%.
  • AHP-2 infection is characterized by periodic symptomatic or asymptomatic virus isolation and the appearance of painful genital ulcers. In addition, it was shown that VGP-2 three times increases the likelihood of infection with the human immunodeficiency virus and accelerates the progression of the disease.
  • Class IV includes representatives of the enterovirus genus from the picornavirus family and the coronavirus family
  • class V includes the respiratory syncytial virus (RSV) and metapneumovirus of the paramyxovirus family.
  • RSV respiratory syncytial virus
  • SUBSTITUTE SHEET (RULE 26) registered human coronaviruses.
  • HCoV-NL63 NL63
  • HKU1 HCoV-HKUl
  • Rhinoviruses cause inflammatory diseases of the upper respiratory tract in humans and animals, multiplying in the cells of the mucous membrane of the nasopharynx. Rhinoviruses are responsible for at least 80% of colds. In addition to the enormous economic damage (20 million people / hours in the United States annually), rhinovirus infections cause a large number of complications, such as sinusitis and middle ear inflammation, and are often detected by virological examination of children with pneumonia. Also, in asthmatic children, rhinovirus infection causes exacerbation in 80% of cases. In adults, rhinoviruses can cause both exacerbation of asthma and chronic obstructive pulmonary disease, chronic bronchitis, cystic fibrosis. Rhinoviruses were isolated in patients with pneumonia in immunodeficiency states.
  • Enterovirus type 71 was first isolated in 1970-1972. from aseptic meningitis patients and encephalitis patients in California. It is important to note that in severe cases, the virus leads to the development of neurological disorders, such as meningitis, paralysis and encephalitis. The virus spreads in unsanitary conditions. When infected with the EV71 virus
  • enterovirus-71 is one of the most “severe” of the total number of human enteroviruses. This virus can cause large outbreaks with fatal outcomes. There is no vaccine against enterovirus-71, and nonspecific therapy has not been developed.
  • Coxivirus infection is a large group of diseases characterized by severe clinical polymorphism.
  • the manifestation of coxivirus infection can be expressed by meningitis, paralysis, acute respiratory disorders, pneumonia, hemorrhagic conjunctivitis, myocarditis, hepatitis, diabetes and other syndromes.
  • human enteroviruses in the genus Enterovirus are divided into five types (14): 1) poliovirus; 2) human enterovirus A; 3) human enterovirus B; 4) human enterovirus C; 5) human enterovirus D.
  • enterovirus A Kersaki A2-8, 10, 12, 14, 16
  • human enterovirus B Kersaki A9, Koksaki B 1-6
  • human enterovirus C Coxsackie A1, 11, 13, 15, 17-22, 24.
  • Coxsackie viruses like other human enteroviruses, are ubiquitous throughout the world. Temperate countries are characterized by a maximum of their circulation in the summer-autumn season. Viruses have a high degree of invasiveness, which leads to their rapid spread in the human population. Koksaki viruses are often the cause of a “sudden” outbreak in organized children's groups, hospitals, and there is also an intrafamily spread of the infection. An important role in the epidemiology of coxsivirus and other enterovirus infections in humans is played by the high level of variability of the viral genome. The consequence of this is the ability of certain serotypes to cause various pathologies in certain circumstances. On the other hand, the same clinical syndrome may be due to different serotypes and different types of enteroviruses. Large outbreaks result from genetic variation, selection and the rapid spread of altered viruses
  • SUBSTITUTE SHEET (RULE 26) diseases in the etiology of which previously these viruses did not participate, or their circulation was not observed for a long time.
  • the primary reproduction of the Coxsackie virus occurs in the lymphoid tissue of the nasopharynx and intestines. It causes local lesions, expressed by symptoms of acute respiratory infections, herpangins, pharyngitis, etc. The virus is detected in the throat for up to 7 days, and with feces it is excreted 3-4 weeks (with immunodeficiencies - several years). Following the primary reproduction, the stage of viremia occurs, as a result of which the pathogen penetrates the target organs.
  • Coxsackie viruses these can be the brain and back, brain, pia mater, upper respiratory tract, lungs, heart, liver, skin, etc.
  • Coxsackie B viruses can cause severe generalized pathological processes in newborns.
  • Viruses cause the development of the following clinical syndromes: serous meningitis (Koksaki A2, 3, 4, 6, 7, 9, 10, Koksaki B 1-6); acute systemic disease in children with myocarditis and meningoencephalitis (Coxsackie B 1-5); paralysis (Koksaki A1, 2, 5, 7, 8, 9, 21, Koksaki B2-5); Herpangin (Koksaki A2, 3, 4, 5, 6, 8, 10); acute pharyngitis (Koksaki A10, 21); contagious runny nose (Koksaki A21, 24); damage to the upper respiratory tract and pneumonia (Koksaki A9, 16, Koksaki B2-5) (16); pericarditis, myocarditis (Koksaki B 1-5); hepatitis (Koksaki A4, 9, 20, Koksaki B5); diarrhea of newborns and young children (Koksaki A18, 20,
  • the Paramyxovirus family includes representatives of the genus respiviruses (human parainfluenza virus types 1, 2, 3, 4 and 5), pneumoviruses (respiratory syncytial virus) and metapneumoviruses (human metapneumovirus).
  • RSV Respiratory syncytial virus
  • RSV is an important pathogen in infants and young children and is responsible for ⁇ 70% of severe viral bronchiolitis and / or pneumonia, most of which are characterized by wheezing and shortness of breath. These bronchiolitis are the most common cause of hospitalization in the winter season during the first year of a child's life. RSV also causes bronchiolitis, pneumonia, and chronic obstructive pulmonary disease in people of all ages and contributes significantly to excess mortality in the winter season.
  • RSV is a leader in the number of deaths among viral infections. In the United States alone, more than $ 2.4 billion is spent on the treatment of viral diseases of the lower respiratory tract in children. By the first year of life, 50-65% of children become infected with this virus, and by the age of two almost 100% of children become infected. To the high-risk group, in addition to premature newborns and the elderly, people who have diseases of the cardiovascular, respiratory and immune systems belong.
  • Bronchiolitis can also be caused by rhinovirus, coronavirus, influenza virus, parainfluenza, and adenovirus, but RSV is the most common cause of hospitalization for bronchiolitis among all the viruses listed.
  • Adaptive immunity resulting from RSV infection in both children (with an immature immune system) and adults is short-term and does not provide complete antiviral protection. This fact leads to the appearance of reinfection observed throughout life.
  • the blood of newborns in the first months of life contains maternal anti-RSV antibodies.
  • HMPV human metapneumovirus
  • the high-risk group includes the elderly, adults with lung diseases and a defective immune system. HMPV outbreaks have been reported in hospitals, with mortality rates as high as 50% among weakened older adults. In addition, 6-12% of exacerbations of chronic obstructive pulmonary disease were observed. In hematopoietic stem cell transplant recipients, HMPV has been associated with severe idiopathic pneumonia.
  • SUBSTITUTE SHEET (RULE 26) In the total number of acute respiratory infections, parainfluenza viruses account for about 20% in the adult population and 30-40% in young children, second only to the respiratory syncytial virus.
  • parainfluenza viruses 1, 2, 3, 4a and 4c isolated from humans. Variability of antigenic structure is not peculiar to them, like influenza viruses.
  • parainfluenza proceeds as a short-term disease (no more than 3-6 days) without pronounced general intoxication.
  • children often experience hypoxia, lower respiratory tract infection, and neurological manifestations that require hospitalization.
  • diseases can occur in the form of croup, bronchiolitis and pneumonia.
  • Parainfluenza viruses of the 1st and 2nd types are most often associated with croup, while the parainfluenza viruses of the 3rd and 4th types are considered the most pathogenic, which most often causes bronchitis, bronchiolitis and pneumonia.
  • parainfluenza infection in mortality of young children and immunosuppressive adult patients, since, complicated by a bacterial infection, parainfluenza causes death from lower respiratory tract infections in 25-30% of cases in these groups. Reinfection of parainfluenza is possible throughout life.
  • catarrh of the upper respiratory tract The most common cause of catarrh of the upper respiratory tract is a bacterial or viral infection (for example, nasopharyngitis, pharyngitis, laryngitis, runny nose), thus inflammation of the mucous membrane of the nasopharynx, most often an infectious etiology.
  • This disease also includes acute and infectious rhinitis, as well as rhinorrhea (acute runny nose).
  • Nasopharyngitis is the most common manifestation of an acute respiratory infection, associated with limited activity and the need for medical advice. 82% of all acute nasopharyngitis are caused by rhinoviruses.
  • SUBSTITUTE SHEET (RULE 26) severe course of acute respiratory diseases with airway obstruction, especially in children of the first years of life. Particular attention is paid to the role of the respiratory syncytial virus, metapneumovirus, coronavirus, bokavirus, rhinovirus, parainfluenza in the development of obstructive airways syndrome. Their role in the development of acute obstructive airway syndrome in children is undeniable, along with this there is evidence of their role in the development of bronchial asthma in genetically predisposed individuals.
  • Respiratory syncytial virus, metapneumovirus, rhinovirus, parainfluenza, coronaviruses, adenoviruses and herpes virus can cause primary pneumonia, bronchitis, bronchiolitis.
  • Viral diseases of the respiratory tract are often accompanied by a bacterial infection.
  • Respiratory bacterial pathogens are often present in the nasopharynx in healthy people. Damage to the respiratory tract as a result of a viral infection can lead to increased bacterial adhesion in the infected respiratory tract and to secondary bacterial pneumonia, bronchitis, bronchiolitis, tonsillitis, which are serious complications.
  • laryngotracheitis has an infectious nature - it is caused by viruses (adenovirus, influenza, parainfluenza viruses) or bacteria (staphylococcus, streptococcus, pneumococcus, mycoplasma, etc.). Laryngotracheitis can occur as an independent disease or as a complication of the inflammatory process in other parts of the respiratory tract (rhinitis, tonsillitis, sinusitis, etc.).
  • SUBSTITUTE SHEET (RULE 26) peribronchitis, contributes to the formation of deforming bronchitis.
  • ribavirin is a relatively toxic agent that often causes anemia. Its main feature is prolonged deposition in red blood cells. As a result, traces of ribavirin are detected even 6 months after the end of the course of therapy. The teratogenic effect of ribavirin is also mentioned.
  • Effective drugs for the treatment of adenovirus infection do not exist.
  • the licensed drug acyclovir and other derivatives of nucleoside analogues are used for the treatment of hepatitis A, but there is an urgent need to create new, more effective antiviral agents.
  • respiratory diseases can be caused by mixed infections, that is, infectious processes that develop in the body with the simultaneous combined effects of two or more pathogens, such as virus associations, which indicates the need for the development of drugs that are effective simultaneously against such infections.
  • mixed infections that is, infectious processes that develop in the body with the simultaneous combined effects of two or more pathogens, such as virus associations, which indicates the need for the development of drugs that are effective simultaneously against such infections.
  • Etiological agents of mixed infections can be microorganisms of the same family or larger taxa and kingdoms in combinations of the virus-virus, virus-bacterium type, etc.
  • mixed respiratory viral infections including, but not limited to, rhinoviruses, Coxsackie virus, respiratory syncytial virus, human metapneumovirus, parainfluenza, coronavirus, human adenovirus, herpes simplex virus type 1 or 2.
  • the present invention relates to new compounds of General formula I or their pharmaceutically acceptable salts for the prevention and treatment of diseases caused by RNA and / or DNA-containing viruses, moreover, General formula I has the following form:
  • R represents
  • n is an integer of 0, 1 or 2;
  • n is an integer of 0, 1 or 2;
  • R 2 represents H or Ci-C 6 alkyl
  • R 3 and R 4 each independently represents H, O, C 6 alkyl, —NH 2 , -
  • HN C (NH 2 ) NH-, NH 2 S (0) 2 -,
  • R may be optionally substituted with a substituent selected from the group consisting of benzyl, benzyl-OC (O) -, Ci-C 6 alkyl, OH and -NH 2 ;
  • o is an integer of 0 or 2;
  • p is an integer from 0 to 3;
  • R 6 and R 7 each independently represents H, Cj-C 6 alkyl, —C (0) NH 2 —COOH, —CH 2 OH, or Ci-C b alkyl-OH 2 ;
  • R 6 and R 7 may optionally be substituted with one or two C] -C 6 alkyls, -CH (CH (OH) CH 3 ) (C (0) OC 2 H 5 ), -CH (CH (OH) CH 3 ) (COOH), CH (CH (CH 3 ) 2 ) (C (0) OCH 3 ), -CH (CH (CH 3 ) 2 ) (C (0) NH 2 ), -CH (CH 3 ) C ( 0) OCH 3 , - CH (CH 3 ) C (0) NH 2 , -CH (CH 2 CH (CH 3 ) 2 ) (C (0) OCH 3 ),
  • R represents
  • R may be optionally substituted with one or more substituents selected from C 6 alkyl, Ci-C 6 alkoxy, halogen, —COOH, —OH, pyridyl, —O—
  • the present invention relates to the use of a number of compounds of formula I, previously disclosed and falling under the general structural formula of the compounds disclosed in the publication of international application WO 99/01103, for a new purpose. More specifically, the inventors have unexpectedly discovered that the compounds of general formula I can be used as non-toxic antiviral agents for infections caused by viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses or the family of coronaviruses (without limitation listed). In particular, these compounds are the following compounds:
  • the present invention relates to an agent for treating and / or preventing diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA-containing viruses belonging to the adenovirus family and / or a family of herpes viruses, which is a compound of general formula I.
  • the invention further relates to methods for producing compounds of the general formula I or their pharmaceutically acceptable salts, encompasses a method for the prevention and treatment of diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA-containing viruses belonging to the adenovirus family and / or herpes virus family, a method for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis for, conjunctivitis, gastroenteritis, hepatitis, myocarditis, a method for the prevention or treatment of complications of infectious diseases caused by RNA-containing viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses,
  • SUBSTITUTE SHEET (RULE 26) the genus of respiviruses or the genus of alpha-coronaviruses, and / or DNA-containing viruses belonging to the adenovirus family and / or the herpesvirus family, a method for the prevention or treatment of rhinorrhea, acute and infectious rhinitis, pharyngitis, nasopharyngitis, tonsillitis, laryngitis, laryngotracheitis, bronchotracheitis, laryngotracheitis, bronchotracheitis, pneumonia or obstructive airway syndrome, comprising administering to the patient an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof.
  • the invention further relates to a pharmaceutical composition for treating diseases caused by RNA-containing viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA-containing viruses belonging to the family of adenoviruses and / or the family of herpes viruses, compositions for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, conjunctivitis, gastroenteritis, hepatitis, myocarditis, pharm a ceptic composition for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, conjunctivitis, gastroenteritis, hepatitis, myocarditis, a pharmaceutical composition for the prevention or treatment of complications of infectious diseases caused by RNA viruses belonging to the genus
  • the invention also relates to a kit for treating diseases caused by RNA-containing viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus
  • SUBSTITUTE SHEET (RULE 26) alpha-coronaviruses and / or DNA-containing viruses belonging to the adenovirus family and / or herpes virus family, a kit for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, conjunctivitis, gastroenteritis, hepatitis, myocarditis, a kit for prevention or treatment diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA soda containing viruses that belong to the adenovirus family and / or herpes virus family, a kit for the prevention or treatment of rhinorrhea, acute and infectious rhinitis, pharyngitis, nasopharyngitis, tonsillitis, laryngitis
  • the invention relates to the use of compounds of general formula I or their pharmaceutically acceptable salts for the manufacture of a medicament for the treatment of diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA -containing viruses belonging to the adenovirus family and / or the herpes virus family.
  • the invention also includes the use of compounds of general formula I or their pharmaceutically acceptable salts for the manufacture of a medicament for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, conjunctivitis, gastroenteritis, hepatitis, myocarditis.
  • the invention also includes the use of compounds of general formula I or their pharmaceutically acceptable salts for the manufacture of a medicament for the prophylaxis or treatment of complications of infectious diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA viruses belonging to RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA viruses belonging to
  • SUBSTITUTE SHEET (RULE 26) the adenovirus family and / or the herpes virus family.
  • the invention also includes the use of compounds of general formula I or their pharmaceutically acceptable salts for the manufacture of a medicament for the prevention or treatment of rhinorrhea, acute and infectious rhinitis, pharyngitis, nasopharyngitis, tonsillitis, laryngitis, laryngotracheitis, laryngotracheobronchitis, bronchitis, bronchiolitis, pneumonia or obstructive syndrome .
  • the present invention relates to compounds of the general formula I, which corresponds to the following formula
  • t is an integer of 0, 1 or 2;
  • n is an integer of 0, 1 or 2;
  • R 2 represents H or Ci-C 6 alkyl
  • R represents —COOH, —C (0) NH 2 ,
  • R 5 may optionally be substituted with a substituent selected from the group consisting of benzyl, benzyl-OC (O) -, Ci-C 6 alkyl, OH and -NH 2 ;
  • o is an integer of 0 or 2;
  • p is an integer from 0 to 3;
  • R 6 and R 7 each independently represents H, QQ alkyl, —C (0) NH 2 , —COOH, —CH 2 OH, or Ci-C 6 alkyl- ⁇ .;
  • R 6 and R 7 may optionally be substituted with one or two CpC 6 alkyls, —CH (CH (OH) CH 3 ) (C (0) OC 2 H 5 ), —CH (CH (OH) CH 3 ) (COOH ), CH (CH (CH 3 ) 2 ) (C (0) OCH 3 ), -CH (CH (CH 3 ) 2 ) (C (0) NH 2 ), -CH (CH 3 ) C (0) OCH 3 , - CH (CH 3 ) C (0) NH 2 , -CH (CH 2 CH (CH 3 ) 2 ) (C (0) OCH 3 ),
  • R may be optionally substituted with one or more substituents selected from CpC 6 alkyl, Ci-C 6 alkoxy, halogen, —COOH, —OH, pyridyl, —O-benzyl and phenyl;
  • the compounds of general formula I according to the invention are administered in solid dosage form.
  • the present invention also relates to methods for producing compounds of general formula I or their pharmaceutically acceptable salts.
  • the present invention relates to a method for preparing compounds of general formula I related to dicarboxylic acid monoamides or pharmaceutically acceptable salts thereof, comprising reacting the corresponding anhydride with an amine or dipeptide in a suitable organic solvent, optionally in the presence of an organic base.
  • the present invention relates to a method for producing compounds of general formula I related to Ci-C b alkylamides or their pharmaceutically acceptable salts, comprising reacting an appropriate amine containing a Ci-C 6 amino substituent on an amino group with glutaric anhydride in an organic solvent.
  • the present invention relates to methods for producing compounds
  • SUBSTITUTE SHEET (RULE 26) general formula I, relating to dicarboxylic acid amides containing a carboxyl group substituted with Ci-C 6 alkyl in the glutary residue, or their pharmaceutically acceptable salts, including:
  • the present invention relates to a method for producing compounds of General formula I related to dicarboxylic acid amides containing mono- or dimethyl substituents in the glutary residue, or their pharmaceutically acceptable salts, including:
  • the present invention relates to a method for producing compounds of general formula I related to dicarboxylic acid amides containing a hydroxyl group in the a position as a substituent on the glutary residue, or their pharmaceutically acceptable salts, including:
  • the present invention relates to a method for producing compounds of General formula I related to glutaryl derivatives of dipeptides or their pharmaceutically acceptable salts according to claim 1, including:
  • the present invention relates to a method for producing compounds of General formula I related to derivatives of ⁇ -aminobutyric acid and the corresponding amine or their pharmaceutically acceptable salts, including:
  • the present invention relates to methods for producing compounds of general formula I related to derivatives of pyroglutamic acid, N-acetyl-glutamic acid at the ⁇ -carboxyl group or glutamic acid at the ⁇ -carboxyl group, 3-aminosulfonylpropionic acid and the corresponding amine or their pharmaceutically acceptable salts
  • the present invention relates to methods for preparing compounds of the general formula I related to amides formed by 3- (4-imidazolyl) acrylic acid and 3- (4-imidazolyl) propionic acid and the corresponding amino acid: 2-aminopentanoic acid, 4-aminobutyric acid and 6 aminohexanoic acid or pharmaceutically acceptable salts thereof
  • (1) the acid chloride method including:
  • reaction consisting in the use of condensing agents, preferably 1, G-carbonyldiimidazole.
  • condensing agents preferably 1, G-carbonyldiimidazole.
  • the reaction is carried out in organic solvents in the presence of an organic base and by heating, preferably up to 80 ° C.
  • the protection of the nitrogen atom in the heterocycles is used, for example, a carbamate-type protecting group such as tert-butoxycarbonyl (Boe), and
  • the invention further encompasses a method for the prevention and treatment of diseases caused by RNA-containing viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA-containing viruses belonging to the family of adenoviruses and / or the herpesvirus family, comprising administering to the patient an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof.
  • a virus belonging to the genus enteroviruses can be selected from the group consisting of rhinoviruses, Coxsackie viruses and enterovirus type 71.
  • the virus belonging to the genus pneumoviruses is a respiratory syncytial virus, and to the genus metapneumoviruses it is a human metapneumovirus.
  • a virus belonging to the genus respiviruses is a parainfluenza.
  • a virus belonging to the genus alpha-coronaviruses is a coronavirus.
  • the adenovirus family includes the genus Mastadenovirus, which includes human adenovirus.
  • the herpesvirus family includes the genus simplexvirus, to which the herpes simplex viruses of the 1st and 2nd types belong (VGP-1 and VGP-2).
  • the invention further relates to methods for producing compounds of the general formula I or their pharmaceutically acceptable salts, encompasses a method for the prevention and treatment of diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA-containing viruses belonging to the adenovirus family and / or herpes virus family, a method for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis for, conjunctivitis, gastroenteritis, hepatitis, myocarditis, a method for the prevention or treatment of complications of infectious diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronavirus
  • SUBSTITUTE SHEET (RULE 26) or treating rhinorrhea, acute and infectious rhinitis, pharyngitis, nasopharyngitis, tonsillitis, laryngitis, laryngotracheitis, laryngotracheobronchitis, bronchitis, bronchiolitis, pneumonia or obstructive airways syndrome, comprising administering to the patient an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof.
  • the dose of a compound of general formula I or a pharmaceutically acceptable salt thereof may be about 0.1-30, preferably 0.1-10 mg / kg, body weight of the patient. In this case, a single dose of the compound of general formula I may be approximately 2-300 mg.
  • a preferred duration of administration of a compound of general formula I is from 3 days to 14 days.
  • the invention further relates to a pharmaceutical composition for treating diseases caused by RNA-containing viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses and / or DNA-containing viruses belonging to the family of adenoviruses and / or the family of herpes viruses an effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof; and pharmaceutically acceptable carriers and excipients.
  • An effective amount of a compound of general formula I or a pharmaceutically acceptable salt thereof is preferably 0.1-30 mg / kg body weight. In this case, the dose of the compound of general formula I can be 2-300 mg with the introduction of 1 time per day.
  • the invention further relates to a pharmaceutical composition for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, conjunctivitis, gastroenteritis, hepatitis, myocarditis, a pharmaceutical composition for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, conjunctivitis, gastroenteritis, hepatitis , myocarditis, pharmaceutical composition for the prevention or treatment of complications of infectious diseases caused by RNA-containing virus and belonging to the genus enterovirus, metapneumovirus, pneumovirus genus, genus or respirovirusov
  • SUBSTITUTE SHEET (RULE 26) the family of adenoviruses and / or the family of herpes viruses, a pharmaceutical composition for the prophylaxis or treatment of rhinorrhea, acute and infectious rhinitis, pharyngitis, nasopharyngitis, tonsillitis, laryngitis, laryngotracheitis, laryngotracheobronchitis, bronchitis, bronchiolitis, pneumonia, an amount of a compound of the general formative or obstructive, I or a pharmaceutically acceptable salt thereof.
  • the invention also relates to a kit for treating diseases caused by RNA-containing viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA-containing viruses belonging to the family of adenoviruses and / or the family of herpes viruses comprising invention and instructions for its use.
  • the invention also relates to a kit for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, conjunctivitis, gastroenteritis, hepatitis, myocarditis, a kit for the prevention or treatment of complications of infectious diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, pneumoviruses, the genus respiviruses, or the genus alpha-coronaviruses, and / or DNA-containing viruses belonging to the adenovirus family and / or the herpes virus family, boron for the prevention or treatment of rhinorrhea, acute and infectious rhinitis, pharyngitis, nasopharyngitis, tonsillitis, laryngitis, laryngotracheitis, laryngotracheobronchitis, bronchitis, bronchiolitis, pneumonia or obstructive air
  • the invention relates to the use of compounds of the general formula I or their pharmaceutically acceptable salts for the manufacture of a pharmaceutical composition for the treatment of diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA -containing viruses belonging to the adenovirus family and / or the herpes virus family.
  • Invention also proposes of viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses,
  • SUBSTITUTE SHEET includes the use of compounds of general formula I or their pharmaceutically acceptable salts for the manufacture of a medicament for the prevention or treatment of exacerbation of asthma, chronic obstructive pulmonary disease, cystic fibrosis, conjunctivitis, gastroenteritis, hepatitis, myocarditis.
  • the invention also includes the use of compounds of general formula I or their pharmaceutically acceptable salts for the manufacture of a medicament for the prophylaxis or treatment of complications of infectious diseases caused by RNA viruses belonging to the genus enteroviruses, metapneumoviruses, the genus pneumoviruses, the genus respiviruses or the genus alpha-coronaviruses, and / or DNA viruses belonging to the adenovirus family and / or the herpes virus family.
  • the invention also includes the use of compounds of general formula I or their pharmaceutically acceptable salts for the manufacture of a medicament for the prevention or treatment of rhinorrhea, acute and infectious rhinitis, pharyngitis, nasopharyngitis, tonsillitis, laryngitis, laryngotracheitis, laryngotracheobronchitis, bronchitis, bronchiolitis, pneumonia or obstructive syndrome .
  • salts of the compounds of general formula I their salts with alkali and alkaline earth metals, preferably sodium, potassium, lithium salts, can be used in the present invention.
  • additive salts of organic acids e.g., formate, acetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.
  • inorganic acid addition salts e.g., hydrochloride, hydrobromide
  • sulfate, phosphate, etc. salts with amino acids (for example, aspartic acid salt, glutamic acid salt, etc.), preferably hydrochlorides and acetates.
  • the compounds of general formula I or a salt thereof are administered in an effective amount that provides the desired therapeutic result.
  • the compounds of general formula I or their salts can be administered to a patient in doses ranging from 0.1 to 30 mg / kg of human body weight per day,
  • SUBSTITUTE SHEET (RULE 26) preferably in doses of 0.3 to 1.5 mg / kg one or more times per day.
  • the specific dose for each particular patient will depend on many factors, such as age, body weight, gender, general health status and diet of the patient, time and method of administering the drug, its rate of excretion from the body, and the severity of the disease in the individual being treated.
  • compositions of the present invention contain compounds of general formula I or their pharmaceutically acceptable salts in an amount effective to achieve the desired result, and can be prepared in unit dosage forms (for example, in solid, semi-solid or liquid forms) containing compounds of general formula I or their salts as an active ingredient in admixture with a carrier or excipient suitable for intramuscular, intravenous, oral, sublingual, inhalation, intranasal , intrarectal and transdermal application.
  • the active ingredient may be included in the composition along with commonly used non-toxic pharmaceutically acceptable carriers suitable for the manufacture of solutions, tablets, pills, capsules, dragees, suppositories, emulsions, suspensions, ointments, gels, plasters and any other dosage forms.
  • Various substances can be used as fillers, such as saccharides, for example glucose, lactose or sucrose, mannitol or sorbitol, cellulose derivatives and / or calcium phosphates, for example tricalcium phosphate or calcium acid phosphate; as a binder component, starch paste, for example, corn, wheat, rice, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone can be used. If necessary, disintegrating agents such as the aforementioned starches and carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, can be used.
  • saccharides for example glucose, lactose or sucrose, mannitol or sorbitol, cellulose derivatives and / or calcium phosphates, for example tricalcium phosphate or calcium acid
  • Optional additives such as flow control agents and lubricants such as silica may be used.
  • SUBSTITUTE SHEET (RULE 26) talc, stearic acid and its salts, such as magnesium stearate or calcium stearate, and / or propylene glycol.
  • additives As additives, stabilizers, thickeners, colorants and perfumes can also be used.
  • hydrocarbon ointment bases such as white and yellow petroleum jelly (Vaselinum album, Vaselinum flavum), liquid paraffin (Oleum Vaselini), white and liquid ointment (Unguentum album, Unguentum flavum), and as additives for giving more dense consistency - such as paraffin wax and wax; absorbent ointment bases such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (Unguentum leniens); ointment bases washable with water, such as hydrophilic ointment (Unguentum hydrophylum); water-soluble ointment bases, such as polyethylene glycol ointment (Unguentum Glycolis Polyaethyleni), bentonite bases and others.
  • absorbent ointment bases such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (
  • methyl cellulose sodium carboxymethyl cellulose, hydroxypropyl cellulose, polyethylene glycol or polyethylene oxide, carbopol can be used.
  • water-insoluble bases such as cocoa butter can be used; bases soluble in water or miscible with water, such as gelatin-glycerol or polyethylene oxide; combined bases - soap-glycerin.
  • the amount of active ingredient used in combination with a carrier may vary depending on the recipient being treated, on the particular route of administration of the drug.
  • the content of the active agent in them is 0.1-5%.
  • diluents 0.9% sodium chloride solution, distilled water, novocaine solution for injection, Ringer's solution, glucose solution, specific additives for dissolution can be used.
  • Dosage forms of the present invention are prepared according to standard procedures, such as, for example, mixing, granulating, dragee forming, dissolving and lyophilization processes.
  • alkyl means a saturated straight or branched hydrocarbon. In some embodiments, implementation, alkyl groups contain 1-6 carbon atoms. In other embodiments, implementation, alkyl groups contain 1-5 carbon atoms. In yet other embodiments, the alkyl groups contain 1-4 carbon atoms, and in still other embodiments, the alkyl groups contain 1-3 carbon atoms.
  • alkoxy refers to an alkyl group, as defined above, attached to the molecule via an oxygen atom (“alkoxy,” for example, —O-alkyl).
  • LC MS-system of analysis of multicomponent mixtures UPLC / MS Shimadzu 2020, including: Analytical HPLC SVM-20A chromatograph, LC-30AD pumps, SIL-30AC autosampler, SPD-M20A detectors, ELSD-LTII (evaporative light scattering detector) and mass spectrometer LCMS-20.
  • LC MS-system of analysis of multicomponent mixtures UPLC / MS Shimadzu 2020, including: chromatograph (Surveyor MSQ, manufacturer Thermo Fisher Scientific), pumps (LC Pump, manufacturer Thermo Fisher Scientific), autosampler (PAL system, manufacturer STS analytics), detectors (Surveyor PDA Plus, manufacturer Thermo Fisher) and mass spectrometer (Surveyor MSQ, manufacturer Thermo Fisher Scientific).
  • Analytical reverse-phase HPLC was performed using an Shimadzu HPLC multicomponent mixtures analysis system including: Analytical HPLC SVM-20A chromatograph, LC-20AD pumps, SIL-20A autosampler, SPD-20A UV detector.
  • Analytical reverse-phase HPLC was performed using an analysis system of multicomponent mixtures of organic origin, including: chromatograph (Agilent 1100), pumps (Hewlett-Packard series 1100, Bin Pump G1312A), UV detector (DAD G1315B Agilent 1100).
  • Dicarboxylic acid monoamides were prepared by reacting the corresponding anhydride with an amine or dipeptide in an organic solvent at different temperature conditions with or without an organic base. In some cases, NH-protected heterocycle amine derivatives have been used. Usually used Remedy. Preferred organic solvents for the condensation reaction are tetrahydrofuran, chloroform, methylene chloride, ⁇ , ⁇ -dimethylformamide, dichloromethane, acetonitrile and a mixture of dioxane with ⁇ , ⁇ -dimethylformamide in a 3: 1 ratio. The reaction is preferably carried out under cooling to 0 ° C or 3-5 ° C, at room temperature or when heating to 45 ° C or 60 ° C, and also at the boiling point of the solvent.
  • Ci-C b dicarboxylic acid alkylamides were obtained by reacting the corresponding amine containing a C 6 alkyl substituent in the amino group with glutaric anhydride in an organic solvent, mainly in isopropanol, upon cooling.
  • Amides of dicarboxylic acids containing a carboxyl group substituted with C 6 alkyl in the glutaryl residue were obtained by reacting the corresponding anhydride with an amine, optionally in a suitable organic solvent, by boiling. Then, the resulting amide was suspended in Ci-C 6 alcohol, and trimethylchlorosilane was added dropwise at room temperature.
  • Amides of dicarboxylic acids containing mono- or dimethyl substituents in the glutary residue were obtained by opening mono- or dimethyl-substituted glutaric anhydride by stirring it in methanol at room temperature for 24 hours. Then, mono- or dimethyl substituted monomethyl ester of glutaric acid was introduced into interaction with the corresponding amine in organic solvents, mainly ⁇ , ⁇ -dimethylformamide, in the presence of a condensing agent, mainly with 1, G-carbonyldiimidazole.
  • Amides of dicarboxylic acids containing a hydroxyl group in the ⁇ -position as a substituent in the glutary residue were obtained using 5-oxotetrahydrofuran-2-carbonyl chloride obtained from 5-oxotetrahydrofuran-2-carboxylic acid by its interaction with oxolyl chloride in an organic solvent under cooling and then 5-oxotetrahydrofuran-2-carbonyl chloride was reacted with the corresponding amine in an organic solvent in the presence of potash, followed by hydrolysis of the lactone in the presence of alkali to the target of the amide.
  • dipeptides were first synthesized based on di-Boc-protected histidine and the corresponding amino acid by the method of activated para-nitrophenyl ethers in ⁇ , ⁇ -dimethylformamide. Boc protection was removed by treatment of the protected dipeptide with trifluoroacetic acid.
  • the glutaryl derivative of the dipeptide was prepared by adding glutaric anhydride to the trifluoroacetate derivative of the dipeptide in ⁇ , ⁇ -dimethylformamide in the presence of 2 equivalents of ⁇ -methylmorpholine.
  • SUBSTITUTE SHEET (RULE 26) synthesized using condensing agents, mainly using 1, G-carbonyldiimidosole.
  • a protected derivative of ⁇ -aminobutyric acid mainly ⁇ -Boc-aminobutyric acid
  • the reaction of N-Boc- ⁇ -aminobutyric acid with 1, G-carbonyldiimidozole gives an activated derivative, imidazolid ⁇ -Boc-y-aminobutyric acid, which reacts with the corresponding amine.
  • Both reactions are carried out in anhydrous organic solvents, mainly in anhydrous acetonitrile.
  • the condensation reaction is carried out with heating, mainly at 45 ° C.
  • the acid chloride method is prepared using predominantly thionyl chloride, the resulting acid chloride is reacted without further purification with the corresponding amino acid in an anhydrous organic solvent at room temperature;
  • SUBSTITUTE SHEET (RULE 26) (2) by the method of using condensing agents, preferably 1, G-carbonyldiimidazole.
  • the reaction is carried out in organic solvents in the presence of an organic base and by heating, preferably up to 80 ° C.
  • the precipitate was dissolved in 25 ml of trifluoroacetic acid, kept for 1 hour, evaporated, the residue was triturated with ether, filtered, dissolved in 50 ml of dimethylformamide, NMM was added to pH 8.5, 5.14 g (10.8 mmol) of paranitrophenyl was added to the solution di-BOC-b-histidine ester, the reaction mixture was left overnight at room temperature, dimethylformamide was evaporated, the residue was dissolved in 10 ml of an ethyl acetate-hexane 8 + 2 ml mixture and passed through a 3x17 cm column filled with a suspension of silica gel in the same mixture.
  • the dipeptide amide was dissolved in 25 ml of trifluoroacetic acid, kept for 1 hour at room temperature, evaporated, the residue was triturated with ether, filtered, dissolved in 25 ml of dimethylformamide, NMM was added to pH-8.5, three portions were added to the resulting solution with an interval of 15- 20 minutes 1, 14 g (10 mmol) of glutaric anhydride, the reaction mixture was kept for 2 hours at room temperature, evaporated, 100 ml of ethyl acetate was added to the residue, left overnight, the precipitate was filtered off, dissolved in 100 ml of water, extracted with 50 ml of ethyl acetate and the aqueous layer was evaporated to half volume, treated with charcoal, evaporated, dissolved in 100 ml of 2% acetic acid and lyophilized.
  • the reaction mixture was stirred for 4 hours at 45 ° C, the solvent was removed in vacuo, the residue was dissolved in 300 ml of ether, washed with a saturated aqueous solution of sodium bicarbonate (3x 100 ml). The organic layer was dried over sodium sulfate, the solvent was removed in vacuo, and the residue was dried in vacuo of an oil pump to constant weight. The residue was dissolved in 80 ml of anhydrous ether, and 35 ml of a 5% solution of hydrogen chloride in anhydrous methanol was added.
  • Acid 1 (1 g, 0.007 mol) was added to 5 ml of cold thionyl chloride in small portions with vigorous stirring. After adding the entire amount of acid 1, the reaction mixture was stirred at the boil for 3-
  • the starting acid chloride of acid 2 (1.4 g, 0.009 mol) was suspended in dry DMF and amine hydrochloride 3 (1, 34 g, 0.0098 mol) and triethylamine (4 ml, 0.036 mol) were added with stirring. The reaction mixture was stirred for 10 hours at room temperature. Upon completion of the reaction, triethylamine hydrochloride was filtered off, the solvent was removed in vacuo under reduced pressure. The residue was purified using silica gel column chromatography, the solvent system was methylene chloride and methanol (15: 1). The yield of pure intermediate 4 was 0.65 g (35%).
  • mice Male white mice weighing 6-7 g. Animals were infected with the virus intramuscularly in a volume of 0.1 ml / mouse. In the experiment, a dose was used to infect 10LD 50 , causing mortality in mice.
  • the ability of the compounds to exert a therapeutic effect was judged by the death of mice infected with the HCXV A2 virus in the experimental group compared with the group of animals not receiving treatment.
  • mice were injected with saline as a placebo.
  • Negative controls were intact animals that were kept under the same conditions as the experimental groups in a separate room.
  • mice For the experiment, groups of 14-15 mice each were formed. Compounds were administered at a dose of 30 mg / kg body weight. The test substances were administered orally, 1 time per day, for 7 days (the first administration - 24 hours after infection). Observation of animals was carried out for 15 days, daily weighing and recording the mortality of animals.
  • mice were infected with the virus at a dose of 5.0 logTCIDso intranasally under mild ether anesthesia in a volume of 0.05 ml / mouse.
  • the studied compounds were administered to animals orally 1 time per day for 5 days according to the treatment regimen at a dose of 30 mg / kg.
  • the first administration was carried out 24 hours after infection.
  • Mice were injected with saline as a placebo.
  • Negative controls were intact animals that were kept in a separate room under the same conditions as the experimental groups.
  • the experimental groups contained 12 mice. Ribavirin at a dose of 40 mg / kg served as a comparison drug.
  • Evaluation of the antiviral activity of the studied compounds was carried out according to the effectiveness of preventing weight loss and suppressing the reproduction of hRSV in the lungs of infected mice by measuring the viral titer in the experimental groups compared with the control on the 5th and 7th days after infection.
  • mice The average body weight of mice on the 5th and 7th day after
  • the therapeutic effect of the compounds of general formula I was evaluated by their ability to suppress the reproduction of hRSV virus in the lungs of mice 5 and 7 days after infection.
  • the virus titer was determined by titration of a 10% suspension of the lungs on a culture of Hep-2 cells. The result was taken into account after 2 days of incubation at 37 ° C according to the CPD.
  • the results of determining the infectious activity of hRSV in mouse lung suspensions in a Hep-2 cell culture after application of the test compounds and the comparative preparation are presented in Table 5.
  • the antiviral activity of chemical compounds against the respiratory syncytial virus of human was evaluated on a model of viral pneumonia in Balb / c mice.
  • the virus was administered intranasally to animals in a volume of 50 ⁇ l under light ether anesthesia.
  • the animals were injected intraperitoneally with cyclophosphamide
  • SUBSTITUTE SHEET (RULE 26) dose of 100 mg / kg.
  • the studied compounds were used according to the treatment regimen once a day at a dose of 30 mg / kg for 5 days, starting 24 hours after infection.
  • the activity of the compounds was evaluated by reducing the edema of an infected respiratory syncytial lung virus compared with the control on the fifth day after infection.
  • Ribavirin 50 1.75 ⁇ 0.47 *
  • Ribavirin 50 1.00 ⁇ 0.17 *
  • the virus was pre-titrated in mice, then the mice were infected and the test compounds were orally administered. On the 4th day after infection, the infectious titer of the virus was evaluated by titration of a pulmonary suspension in a Hela cell culture. Infectious titer of hRV virus in the lungs of animals of the experimental group compared to the group of animals not receiving treatment was determined by the CPD.
  • the studied compounds and placebo were administered to animals orally 1 time per day, for 4 days, starting 12 hours after infection.
  • Compounds were administered at a dose of 30 mg / kg body weight of the animal.
  • As a negative control intact animals were used, which were kept in a separate room under the same conditions as the experimental groups.
  • the antiviral activity of the test compounds was evaluated to reduce the infectious activity of the virus, as determined in a Hela cell culture.
  • mice The study of the weight of the lungs of mice showed that during the experiment, the weight of the lungs of infected mice exceeded the weight of the lungs of intact animals, indicating an actively ongoing infectious process. Under the influence of the studied compounds of general formula I, the weight of the lungs of the animals significantly differed (was lower) from the viral control group and practically did not differ from the weight of the lungs in intact mice.
  • SUBSTITUTE SHEET (RULE 26)
  • a Sendai parainfluenza virus strain was used.
  • Outbred white mice of males weighing 10-12 g were infected intranasally under mild ether anesthesia in a volume of 0.05 ml / mouse Sendai parainfluenza strain adapted to mice.
  • a dose of 10LD50 virus was used, causing 70-80% mortality in mice.
  • 20 mice in each group were used. Intact animals that were kept under the same conditions as the experimental groups in a separate room were used as a negative control.
  • the antiviral effect of the compounds of general formula I was studied by oral administration of substances to infected animals once a day at a dose of 30 mg / kg / mouse 24, 48, 72, 96 and 120 hours after infection with the virus.
  • the control group mice were given a placebo (0.2 ml of physiological saline) under the same conditions. The animals were observed for 14 days after infection, given the death of mice in groups.
  • Each animal was inspected daily.
  • the examination included an assessment of the general behavior and condition of the animals. On the days of drug administration, the examination was carried out before the drug was administered at the prescribed time and approximately 2 hours after the administration. The handling of animals was carried out in accordance with international standards.
  • the activity of the compounds was evaluated by comparing mortality in groups of animals that took the drug and placebo.
  • mice Females, males, 7-8 g in weight, were infected with Uc (intracerebral route of administration) in a volume of 30 ⁇ l / mouse containing a dose of 10LD50. For infection, a dose of 10LD50 was used, causing 100% mortality in mice.
  • the experimental groups contained 20 mice. Intact animals that were kept under the same conditions as the experimental groups in a separate room were used as a negative control.
  • the antiviral effect of the compounds of general formula I was studied by oral administration of substances to infected animals once a day at a dose of 30 mg / kg / mouse 24, 48, 72, 96 and 120 hours after infection of animals with the virus.
  • the control group mice were given a placebo (0.2 ml of physiological saline) under the same conditions. The animals were observed for 14 days after infection, given the death of mice in groups.
  • SUBSTITUTE SHEET (RULE 26) general behavior and condition of animals. The handling of animals was carried out in accordance with international standards.
  • the activity of the compounds was evaluated by comparing mortality in groups of animals that took the drug and placebo.
  • Test compounds were orally administered to animals at a dose of 30 mg / kg body weight. Animals of the control group received saline. The drugs were administered orally 1 time per day for 5 days. Treatment of animals began 24 hours after infection.
  • Induction of nasopharyngitis was carried out by intranasal administration of a formalin solution to rats in each nasal passage.
  • a clinical examination of each animal was carried out daily at least 2 times a day.
  • SUBSTITUTE SHEET (RULE 26) changes in the control group of animals, characterizing the development of an acute inflammatory process in the upper respiratory tract.
  • the pathology caused was characterized by hyperplasia, an increase in the number of goblet cells, severe infiltration by monononuclear cells and leukocytes, and hyperproduction of mucus by the glands of the submucosa.
  • mice Females infected with Staphylococcus aureus (strain adapted to mice).
  • the administration of compounds to mice was started 5 days before infection orally in doses of 15 and 30 mg / kg in a volume of 0.2 ml.
  • mice were infected intranasally under mild ether anesthesia by the administration of Staphylococcus aureus at a dose of 10 9 CFU in a volume of 0.05 ml.
  • Ampicillin administered once intravenously at a dose of 20 mg / kg, was used as a comparison drug.
  • mice infected intranasally with Staphylococcus aureus and treated with PBS served as a control. After two days, the mice were sacrificed, the chest cavity was opened and lung prints were made on Petri dishes with Colombian agar. After incubation for 24 hours at 36 ° C, the presence (or absence) of bacterial growth of Staphylococcus aureus was recorded in comparison with the control. The intensity of bacterial growth was evaluated in points and expressed in%.
  • SUBSTITUTE SHEET (RULE 26) G-200 at a dose of 5 mg / kg.
  • the test compounds were administered to animals intragastrically four times: 24 and 1 hour before, as well as 24 and 45 hours after administration of Sephadex. 48 hours after Sephadex inhalation, animals were euthanized, and the lung was taken for histological analysis. Sections 4 ⁇ m thick were stained with hematoxylin and eosin. Inflammatory changes in the lungs were evaluated. The assessment was carried out on a 5-point scale:
  • the number of rats in the group is 7-10 pcs.
  • test compounds of general formula I showed activity in the range of test doses.
  • the compounds of the invention can be administered orally, intranasally, intramuscularly or intravenously in unit dosage form containing non-toxic pharmaceutically acceptable carriers.
  • These compounds may be administered to a patient in doses of 0.1 to 10 mg / kg body weight per day, preferably in doses of 0.5 to 5 mg / kg, one or more times per day.
  • SUBSTITUTE SHEET (RULE 26) The patient will depend on many factors, including age, body weight, gender, general health status and diet of the patient, the time and method of administering the drug, its rate of excretion from the body, and the severity of the disease in the patient undergoing treatment.
  • compositions contain the compounds of the invention in an amount effective to achieve a positive result, and can be administered in unit dosage forms (e.g., in solid, semi-solid or liquid forms) containing the compound as an active ingredient in admixture with a carrier or excipient, suitable for oral, intramuscular or intravenous administration.
  • a carrier or excipient suitable for oral, intramuscular or intravenous administration.
  • the active ingredient may be included in the composition along with commonly used non-toxic pharmaceutically acceptable carriers suitable for the manufacture of solutions, tablets, pills, capsules, dragees and any other dosage forms.
  • binders can be used such as starch paste, for example, corn, wheat, rice, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone.
  • disintegrating agents such as the aforementioned starches and carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate, can be used.
  • Optional additives may also be included, for example, flow control agents and lubricants, such as silica, talc, stearic acid and its salts, such as magnesium stearate or calcium stearate, and / or propylene glycol.
  • flow control agents and lubricants such as silica, talc, stearic acid and its salts, such as magnesium stearate or calcium stearate, and / or propylene glycol.
  • additives As additives, stabilizers, thickeners, colorants and perfumes can also be used.
  • SUBSTITUTE SHEET (RULE 26) the active ingredient used in combination with a carrier may vary depending on the patient being treated and on the particular method of administration of the drug.
  • the content of the active agent in them is 0.01-5 wt.%.
  • diluents 0.9% sodium chloride solution, distilled water, novocaine solution for injection, Ringer's solution, glucose solution, specific additives for dissolution can be used.
  • their amount is 5.0-500 mg per standard dosage form.
  • Dosage forms of the compounds of the invention for use in accordance with the present invention are prepared according to standard procedures, such as, for example, mixing, granulation, dragee formation, dissolution and lyophilization.
  • a tablet form is prepared using the following ingredients:
  • the components are mixed and compressed to form tablets.
  • the compound of the invention or its pharmaceutically 1 -100 mg
  • composition of the solution for injection is an example of the composition of the solution for injection:
  • Dosage forms of the compounds of general formula I for use in accordance with the present invention are prepared according to standard procedures, such as, for example, mixing, granulation, dragee formation, dissolution and lyophilization.
  • a tablet form is prepared using the following ingredients:
  • the components are mixed and compressed to form tablets weighing 300 mg each.
  • the compound of General formula I or its salt is 100 mg,
  • SUBSTITUTE SHEET (RULE 26) Lactose (milk sugar), potato starch, colloidal silicon dioxide (Aerosil), magnesium stearate - to obtain a capsule mass of 220 mg
  • the above ingredients are mixed, granulated, granules are placed in hard gelatin capsules in an amount of 220 mg.
  • composition of the solution for injection is an example of the composition of the solution for injection:
  • composition of 1 solution for injection is a composition of 1 solution for injection:
  • isotonic phosphate buffer As a solvent in the preparation of a solution for injection, 0.9% sodium chloride solution, isotonic phosphate buffer can be used. Release form - ampoules, bottles, syringe tubes, “insert”.

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Abstract

L'invention se rapporte au domaine de la médecine et concerne un procédé de prévention et de traitement de maladies induites par des virus contenant de l'ARN et/ou de l'ADN et de maladies assimilées, lequel consiste à utiliser une quantité efficace de composé de la formule générale I ou un sel pharmaceutiquement acceptable de celui-ci. L'invention concerne également des procédés de production de ces composées et de compositions pharmaceutiques pour la prévention ou le traitement de maladies induites par des virus contenant de l'ARN et/ou de l'ADN et contenant une quantité efficace du composé de la formule générale I ou d'un sel pharmaceutiquement acceptable de celui-ci. La présente invention permet d'obtenir un nouvel agent efficace dans le traitement de maladies induites par des virus contenant de l'ARN et appartenant aux genres des entérovirus, des métapneumovirus, des pneumovirus, des respirovirus ou des alpha coronavirus, des virus contenant de l'ADN appartenant à la famille des adénovirus, des virus de l'herpès, ainsi que dans la prévention et le traitement d'une aggravation de l'asthme, des maladies obstructives chroniques de poumons, de la mucoviscidose, de la conjonctivite, de la gastroentérite de l'hépatite, de la myocardite, dans le traitement et la prévention de la rhinorrhée, de la rhinite aigüe ou infectieuse, de la pharyngite de la nasopharyngite, de la tonsillite, de la laryngite, de la laryngotrachéite, de la bronchite de la bronchiolite, de la pneumonie ou d'un syndrome obstructif des voies respiratoires.
PCT/RU2015/000121 2014-03-12 2015-02-27 Composés amides et procédés de leur production et utilisation WO2015137846A1 (fr)

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KR1020187021614A KR20180088510A (ko) 2014-03-12 2015-02-27 아미드 화합물, 및 rna 및/또는 dna 함유 바이러스에 의해 유발된 질환, 및 동반 질환의 예방 및 치료제로서의 용도
FIEP15761359.7T FI3118211T3 (fi) 2014-03-12 2015-02-27 Amidiyhdisteitä, valmistusmenetelmiä ja niiden käyttö aineina hoidettaessa ja ennaltaehkäistäessä rna:ta ja/tai dna:ta sisältävien viruksien aiheuttamia sairauksia sekä samanaikaisia sairauksia
EP18191137.1A EP3431469A1 (fr) 2014-03-12 2015-02-27 Composé amide et son utilisation en tant qu'agent pour le traitement et la prévention de maladies causées par des virus contenant de l'arn et/ou de l'adn et des maladies concomitantes
CA2941900A CA2941900C (fr) 2014-03-12 2015-02-27 Composes d'amide, methode de preparation et utilisation desdits composes comme agents de traitement et de prevention de maladies causees par des virus comportant de l'arn ou de l'adn, et maladies concomitantes
US15/125,460 US20170183318A1 (en) 2014-03-12 2015-02-27 Amide compounds, methods for preparation, and use thereof as agents for the treatment and prevention of diseases caused by rna- and/or dna-containing viruses, and concomitant diseases
MX2016011771A MX2016011771A (es) 2014-03-12 2015-02-27 Compuestos de amida, metodos de preparacion y uso de los mismos como agentes para el tratamiento y prevención de enfermedades ocasionadas por virus que contienen arn y/o adn y enfermedades concomitantes.
CN201580023692.4A CN106459144A (zh) 2014-03-12 2015-02-27 酰胺化合物及其产生方法和用途
SG11201607535VA SG11201607535VA (en) 2014-03-12 2015-02-27 Amide compounds, methods for preparation, and use thereof as agents for the treatment and prevention of diseases caused by rna- and/or dna-containing viruses, and concomitant diseases
EA201691694A EA035545B1 (ru) 2014-03-12 2015-02-27 Амидные соединения, способы получения, применение в качестве средств для лечения и профилактики заболеваний, вызываемых рнк- и/или днк-содержащими вирусами, и сопутствующих заболеваний
ES15761359T ES2938085T3 (es) 2014-03-12 2015-02-27 Compuestos de amida, métodos de preparación y uso de los mismos como agentes para el tratamiento y prevención de enfermedades causadas por virus que contienen ARN y/o ADN y enfermedades concomitantes
KR1020167027752A KR102410255B1 (ko) 2014-03-12 2015-02-27 아미드 화합물, 그의 제조방법, 및 rna 함유 및/또는 dna 함유 바이러스에 의해 유발된 질환, 및 동반 질환의 예방 및 치료제로서의 용도
EP15761359.7A EP3118211B1 (fr) 2014-03-12 2015-02-27 Composés amides, procédés pour leur préparation et leur utilisation comme agents pour le traitement et la prévention de maladies causées par des virus à arn et/ou adn et des maladies concomitantes
JP2016575291A JP2017511374A (ja) 2014-03-12 2015-02-27 Ｒｎａおよび／またはｄｎａ含有ウイルスにより引き起こされる疾患、および合併症の治療および予防のための薬剤としての、アミド化合物、その調製方法、ならびに使用。
AU2015230061A AU2015230061B2 (en) 2014-03-12 2015-02-27 Amide compounds, methods for preparation, and use thereof as agents for the treatment and prevention of diseases caused by RNA- and/or DNA-containing viruses, and concomitant diseases
IL247704A IL247704B (en) 2014-03-12 2015-02-27 Amide compounds, methods for their preparation and use as substances for the treatment and prevention of diseases caused by viruses containing RNA and/or DNA and associated diseases
UAA201610353A UA121468C2 (uk) 2014-03-12 2015-02-27 Амідні сполуки, способи одержання, застосування як засобів для лікування й профілактики захворювань, що викликаються рнк- і/або днк-вмісними вірусами, й супутніх захворювань
AU2018205206A AU2018205206A1 (en) 2014-03-12 2018-07-13 Amide compound and use thereof as an agent for the treatment and prevention of diseases caused by RNA- and/or DNA-containing viruses, and concomitant diseases
US15/998,847 US20180362481A1 (en) 2014-03-12 2018-08-17 Amide compound, methods for preparation, and use thereof as agent for the treatment and prevention of diseases caused by rna- and/or dna-containing viruses, and concomitant diseases

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RU2014109441A RU2628800C2 (ru) 2014-03-12 2014-03-12 Амидные соединения, способы получения, применение в качестве средств для лечения и профилактики заболеваний, вызываемых рнк-содержащими вирусами

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US15/998,847 Division US20180362481A1 (en) 2014-03-12 2018-08-17 Amide compound, methods for preparation, and use thereof as agent for the treatment and prevention of diseases caused by rna- and/or dna-containing viruses, and concomitant diseases

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CN109288837B (zh) 2021-04-30
SG11201607535VA (en) 2016-10-28
UA121468C2 (uk) 2020-06-10
ES2938085T3 (es) 2023-04-04
KR102410255B1 (ko) 2022-06-20
EA201691694A1 (ru) 2017-01-30
EA035545B1 (ru) 2020-07-06
RU2014109441A (ru) 2015-09-20
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CA2941900C (fr) 2022-08-16
JP2017511374A (ja) 2017-04-20
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JP6915911B2 (ja) 2021-08-04
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AU2015230061B2 (en) 2019-09-05
KR20180088510A (ko) 2018-08-03
MX2016011771A (es) 2017-04-27
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